Polio pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: João André Alves Silva, M.D. [2]

Overview

Poliovirus enters the body orally, and infects cells of the gastrointestinal tract, from the mouth to the ileum and mesenterium. After replication, the virus may either be secreted in feces, contributing to the transmission of the disease, or reach the bloodstream, and be transported to other cells of the body, such as those of the reticuloendothelial system. Although the precise mechanism of infection of CNS is not fully understood, the most supported hypothesis is the retrograde axonal transport, according to which the virus enters the axoplasm of a motor neuron, travels to its cell body, where it replicates, and leads to neuron death. In the CNS, poliovirus shows tropism for cells of the anterior horn of the spinal cord, hypothalamus, thalamus, cerebellar vermis, vestibular and deep cerebral nuclei. Death of the motor neuron is responsible for the paralysis often seen in poliomyelitis.

Pathogenesis

Poliovirus enters the body orally and most often infects nearby cells, such as those of the mouth, nose, and throat. It infects cells by binding to an immunoglobulin-like receptor known as CD155 on the cell surface. The most common course of infection is the replication of poliovirus in cells of the gastrointestinal tract, followed by viral shedding in feces. The specific cells of the gastrointestinal tract, where poliovirus replicates, are not known, however, the virus was successfully isolated from lymphatic cells of the GI tract, including:

• Tonsillar cells
• Peyer's patches of the ileum
• Lymph nodes of the mesenterium

The virus enters the bloodstream and migrates to the reticuloendothelial cells across the body. Poliovirus is able to reach the central nervous system in a small fraction of the symptomatic patients. Not only is the disease not a phase of the viral replication cycle, it also does not benefit the virus in any way. The molecular mechanism behind this disease process is not known.

Poliovirus replicates inside monocytes, which allows for secondary hematogenous spread. The pathological mechanism responsible for the clinical manifestations of CNS poliomyelitis is characterized by selective destruction of motor neurons. Depending of the involved site, motor neuron loss may lead to focal or generalized symptoms. Most commonly observed signs and symptoms include asymmetric limb paralysis in spinal polio and respiratory disturbance with cranial nerve defects in bulbar polio.

Although the mechanism of viral spread to the CNS is not fully understood, two main hypotheses have been proposed:

1. Poliovirus diffuses directly through the blood brain barrier from the bloodstream to the CNS, regardless of cellular receptors.
2. Poliovirus is transported from the peripheral muscles to the brain and spinal cord, through retrograde axonal transport. This hypothesis has been experimentally proven in mice, after CD155 transformation.

Retrograde Axonal Transport Hypothesis

Recent discoveries supporting the second hypothesis have been reported:

• Axonal presence of poliovirus, in patients with poliomyelitis, has been reported - This explains the "provocation poliomyelitis" phenomenon, in which muscle trauma, in the presence of viremia, was associated with an higher risk of developing poliomyelitis.
• In mice, genetically transformed to express CD155, after injection of poliovirus in the left limb, viral replication was only noted in the left anterior horn of the spinal cord. Viral replication occurred 33 hours before onset of paralysis. When the sciatic nerve was promptly sectioned after injection of the virus, the predisposition of the implicated leg to be paralyzed was eliminated.
• In the same mice, if poliovirus was injected intravenously, poliomyelitis would manifest first in the limb that had been injured by multiple empty needle injections. This leads to the idea that injured muscle opens a way for the virus to penetrate the terminal of the presynaptic motor neuron.
• Bulbar poliomyelitis following tonsillectomy may possibly be explained by the previously described mechanisms.
• There is over expression of CD155 on the muscle fibers of patients with paralytic poliomyelitis.
• CD155, directly interacts with the dynein retrograde complex, through Tctex-1.

In a neuronal synapse, the rate of endocytosis is related to the level of neuron activity. For the motor neuron, the level of neuron activity at the neuromuscular junction is associated with muscle contraction, therefore, increased muscle activity is related to increased rate of endocytosis. This explains the connection between extreme exercise activity and development of poliomyelitis in patients with viremia, since there is greater probability of viral uptake. Also, since most of CD155 receptors are transported back to the cell body, the virus is carried along, supporting the retrograde transport hypothesis.

Once at the cell body of the neuron, the change from axoplasm to cytoplasm is thought to interfere with the stability of the viral coat, leading to the exposure of the viral RNA. Viral replication interferes with neuron stability, killing the motor neuron. Death of the motor neuron paralyzes the respective muscle fiber. Spread of the virus to nearby neurons will be responsible for the death of these cells.

In the CNS, poliovirus shows tropism for certain pathways and tissues:

• Anterior horn cells of the spinal cord (in severe cases of the disease, the intermediate, intermediolateral and posterior gray columns may also be affected)
• Hypothalamus
• Thalamus
• Vestibular nuclei
• Deep cerebral nuclei
• Reticular formation
• Cerebellar vermis

Lesion distribution in paralytic and non-paralytic cases is the same. Additionally, inflammation can be detected in any affected area of the CNS, supporting the idea that in order to produce clinical manifestations, severe neuron damage must occur. The different clinical forms of poliomyelitis will depend on the most affected area of the CNS. Individual host factors and the neuropathogenicity of the virus influence the severity of the lesions.

Transmission

Poliovirus is mostly transmitted through the fecal-oral route, by ingestion of contaminated food or water, and through pharyngeal secretions. In some instances, the oral-oral route may be relevant.

Poliomyelitis is highly contagious and spreads easily through human-to-human contact. In endemic areas, wild polioviruses can infect virtually the entire human population. Viral particles are excreted in the feces for several weeks, after initial infection.

Although the virus can cross the placenta during pregnancy, the fetus does not appear to be affected by either maternal infection, or polio vaccination. Maternal antibodies can also cross the placenta, providing passive immunity that protects the infant from polio infection during the first few months of life.

Gallery

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  A photomicrograph of skeletal muscle tissue revealing myotonic dystrophic changes as a result of Polio Type III.Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.
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  A photomicrograph of the lumbar spinal cord depicting an infarct due to Polio Type III surrounding the anterior spinal artery.Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.
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  A photomicrograph of the lumbar spinal cord depicting an infarct due to Polio Type III surrounding the anterior spinal artery.Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.
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  A photomicrograph of the lumbar spinal cord depicting degenerative changes due to an infarct caused by Polio Type III.Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.
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  A photomicrograph of the thoracic spinal cord depicting degenerative changes due to Polio Type III.Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.
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  A photomicrograph of the thoracic spinal cord depicting degenerative changes due to Polio Type III.Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.
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  A photomicrograph of the cervical spinal cord in the region of the anterior horn revealing Polio Type III degenerative changes.Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.
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  A photomicrograph of the cervical spinal cord in the region of the anterior horn revealing Polio Type III degenerative changes.Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.
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  A photomicrograph of the cervical spinal cord in the region of the anterior horn revealing Polio Type III degenerative changes.Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.
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  Under a low magnification of 40X, this photomicrograph of a brain tissue specimen, specifically from the pontine region (pons), revealed histopathologic changes in a confirmed polio, or poliomyelitis patient. This tissue section was extracted from the pons at the level of the cranial nerve VI (CN VI) nucleus, which is also known as the abducens nerve.Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.
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  Photomicrograph of the Cervical Spinal Cord Affected by Polio Type III VirusAdapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.